MEMORANDUM OF UNDERSTANDING
Among
The Food and Drug Administration (FDA)
And
The National Institutes of Health
National Institute of Environmental Health Sciences (NIEHS),
Division of the National Toxicology Program (NTP)
And
Health and Environmental Sciences Institute (HESI)

I. PURPOSE

Cardiovascular safety is a significant public health concern and challenge for those seeking to improve the safety of pharmaceuticals. These challenges impact the commercial research and development sector as well as regulators and policy makers. This memorandum of understanding (MOU) is established in support of an overall aim of improving public health through the design and implementation of novel approaches for evaluating cardiovascular liabilities of pharmaceuticals. This MOU provides the framework for collaborative efforts to enable earlier recognition of human-relevant safety liabilities, reduce the use of animals and increase our catalogue of human-relevant biomarkers that can be used for safety monitoring in clinical trials or in other epidemiologic or case control studies. Throughout this document, FDA, NIEHS NTP, and HESI are referred to individually as a “Party” and collectively as the “Parties.”

This MOU states the shared understanding of the Parties as to how they expect to proceed on these issues. It is not a binding agreement. Any joint activities between the government parties (FDA and/or NIEHS NTP) and HESI will be governed by a separate agreement that must comply with applicable laws and regulations governing agreements between Federal government and non-government entities.

II. BACKGROUND

The current assessment approaches to cardiovascular safety evaluation are mostly dependent on traditional animals studies and would benefit from approaches that are more efficient in cost and time as well as more mechanistically informative and human relevant. With engagement of senior scientists from the NTP and FDA Center for Drug Evaluation and Research (CDER), the HESI Cardiac Safety Technical Committee – a consortium of experts in cardiovascular safety evaluation – has been actively leveraging its multi-sector and multi-disciplinary stakeholder base to address this challenge.

This project involves mobilizing experts in cardiovascular toxicology and risk assessment to define relevant xenobiotic-induced ‘failure modes’. These failure modes will be further characterized by their cellular targets and mechanistic pathways. A novel portfolio of non-animal testing platforms and assays will be defined. Those assays will be recruited from commercial and non-commercial capability developers and tested for their reproducibility and usefulness for modeling human outcomes. Confidence in the novel approach will be supported by formal analytical validation, benchmarking against known human outcomes and applying a rational decision-making paradigm.

This MOU serves as the general framework for the scientific and collaborative interactions between the Partners in support the general purposes described above. Additional or modified projects may be Appended to this MOU.

FDA is authorized to enforce the Federal Food, Drug, and Cosmetic Act (the Act) as amended (21 U.S.C. 301, et seq.). In fulfilling its responsibilities under the Act, FDA, among other things, directs its activities toward promoting and protecting the public health by assuring the safety, efficacy, and security of human and  veterinary drugs and medical devices and the safety and security of foods, dietary supplements, cosmetics, and radiological products. FDA also has responsibility for regulating the manufacturing, marketing, and distribution of tobacco products to protect the public health and to reduce tobacco use by minors. To accomplish its mission, FDA must stay abreast of the latest developments in research and communicate with stakeholders about complex scientific and public health issues. Increased development of research, education, and outreach will contribute to FDA’s mission.

The National Institutes of Health is authorized by Section 301 and Title IV of the Public Health Service Act to conduct and support research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of disease and other aspects of human health.

NIEHS NTP provides the scientific basis for programs, activities, and policies that promote health or lead to the prevention of disease. Founded in 1978, NTP plays a critical role in generating, interpreting, and sharing toxicological information about potentially hazardous substances in our environment. NTP strives to remain at the cutting edge of scientific research and the development and application of new technologies for modern toxicology and molecular biology.

HESI is a non-profit 501(c)(3) charitable scientific organization whose mission is to develop science for a safer, more sustainable world. HESI achieves its mission by serving as a neutral and skilled convener of scientists from academic, government, foundations, research institutes, and the commercial sector. Since 1989, HESI programs have helped to build scientific evidence on human and environmental health issues through collaborative and efficient research and expertise-sharing platforms. The HESI Committee on Cardiovascular Safety Assessment – a multi-sector, international initiative - currently involves more than 80 scientific experts committed to improving the relevance, accuracy, and efficiency of cardiovascular safety evaluation.

III.  COMMON UNDERSTANDING OF THE PARTIES

The Parties expect to work together on a number of collaborative projects leveraging the individual and pooled expertise and resources of the Parties. Relevant activities of the Parties could include administrative and logistical support, intellectual input, laboratory investigation, manuscript writing and public presentations.  n their shared efforts to educate and build consensus across government, academic, clinical, NGO, and industry stakeholders, the Parties may elect to share with each other information that is in the public domain and considered non-confidential. Activities contemplated under this MOU are not intended to include group advice to FDA or NIEHS NTP that would be subject to the Federal Advisory Committee Act (FACA), 5 U.S.C. App.

In furtherance of this MOU

A. FDA expects to:

1. Engage in the scientific design, evaluation, and implementation efforts of the program described in this MOU.

2. Provide non-clinical and clinical safety perspective and expertise.

3. Provide regulatory perspective.

B. NIEHS expects to:

1. Engage in the scientific design, evaluation, and implementation efforts of the program described in this MOU.

2. Provide nonclinical safety/hazard characterization perspective and expertise.

3. Provide a link to the environmental safety community.

4. Recruit and support appropriate laboratory investigation as needed.

C. HESI expects to:

1. Engage in the scientific design, evaluation, and implementation efforts of the program described in this MOU.

2. Provide program management and communications support for MOU-related  communications between FDA, NIEHS NTP and the HESI Cardiac Safety Technical Committee.

3. Provide scientific expertise and staff coordination and support to ensure HESI Cardiac Safety Technical Committee input into MOU-related research approaches, data review and interpretations and the development of manuscripts and presentations.

IV. GENERAL PROVISIONS

1. Rights to any inventions resulting from collaborative research will be determined by the separate written research agreements governing the effort, and will comply with current U.S. Government patent regulations and any other applicable statutes and regulations.

2. Institutions within each party may decide to enter into Cooperative Research and Development Agreements (CRADA) specific to particular collaborative projects. The terms of such CRADAs will address Intellectual Property rights.

3. Proprietary and/or nonpublic information will not be disclosed under this MOU, unless such disclosure is permitted by law and is governed by appropriate confidentiality disclosure agreements.

4. Each Party will comply with the other Party's security procedures and policies regarding access to and use of facilities. Any Party may restrict or limit access to its property and facilities at any time and for any reason. All individuals participating in activities under this MOU on FDA property will comply with all applicable Federal statutes and regulations.

5. Under this MOU, joint efforts will be undertaken to support collaborative research and training as permitted under appropriate statutory authority. Before any specific collaboration is initiated or implemented, the Parties shall identify priorities, topics of mutual interest, and develop separate, written supplemental agreements for collaboration and sharing of resources. Where applicable, these agreements may reference this MOU. The terms and conditions of any such agreements will comply with applicable Federal law and regulations, and shall be negotiated and executed by appropriate representatives among parties under procedures that comply with applicable laws and regulations that govern contracts between government agencies and non-goverenment entities..

V. RESOURCES OBLIGATIONS

This MOU represents the broad outline of the FDA, NIEHS NTP, and HESI’s intent to collaborate in areas of mutual interest. All activities that may be undertaken by this MOU are subject to the availability of personnel, resources, and funds. This MOU does not create binding, enforceable obligations against any Party. This MOU does not affect or supersede any existing or future agreements or arrangements among the Parties and does not affect the ability of the Parties to enter other agreements or arrangements related to this MOU.

VI. Liaison Officers

A. For the Food and Drug Administration: Individual's Name: Norman Stockbridge, MD
Organization: Food and Drug Administration
Title: Director. Division of Cardiovascular and Renal Products, CDER
Address: 10903 New Hampshire
Silver Spring, MD 20993
Telephone Number: 301-796-1155

B. For the National Institute of Environmental Health Sciences National Toxicology Program
Name: Brian Berridge, DVM, PhD
Organization: National Institute of Environmental Health Sciences
Title: Associate Director, National Toxicology Program
Address: 111 T. W. Alexander Dr
Research Triangle Park, NC  27709
Telephone Number: 987-287-3111

C. For the Health and Environmental Sciences Institute (HESI)
Name: Syril Pettit, MEM
Organization: Health and Environmental Sciences Institute
Title: Executive Director
Address: 740 15th St, NW, 6th Floor, Washington DC 20005
Telephone Number: 202-659-3306

Each Party may designate new liaisons by notifying the other Party's administrative liaison in writing. If, at any time, an individual designated as a liaison under this agreement becomes unavailable to fulfill those functions, the Parties will name a new liaison within 2 weeks and notify the other Party through the designated administrative liaison.

VII. TERM, TERMINATION AND MODIFICATION

Activities under this MOU will start upon the signature by authorized officials of each Party, and continue for 5 years from the date that all Parties have signed, unless the MOU is modified or terminated. Each party agrees to provide at least a 60-days advance written notice of their intent to modify or terminate this this MOU to the other parties.

VIII. STATUTES, REGULATIONS, RULES AND POLICIES

This MOU and all associated agreements will be subject to the applicable statutes, regulations, rules, and policies under which FDA, NIEHS NTP, and HESI operate.

Approved and Accepted for the National Institute of Environmental Health Sciences
/s/                                                                                                              
Linda Birnbaum, Director,                                                                           
National Toxicology Program

Date
12/17/18

Approved and Accepted for the Food and Drug Administration
/s/
RADM Denise Hinton; Chief Scientist, FDA                                                                                            

Date
2/12/19

Approved and Accepted for the Health and Environmental Sciences Institute
/s/                                                                                                                
Syril D. Pettit, Executive Director      

Date
12/12/18